Application Of In-situ Forming Enzyme-responsive Hydrogel In Cancer Chemotherapy And Postoperative Recurrence Prevention

In-situ forming hydrogels with minimally invasive procedures,encapsulation stability and stimuli-responsive degradation have emerged as promising carriers for local drug delivery.In this paper,nano-drug micelles were loaded into hydrogels and they were used as a local drug delivery system in tumor local chemotherapy and postoperative recurrence prevention.The details are as follows:(1)Using the self-assembly ability of amphiphilic polymer in aqueous solution,doxorubicin(DOX),methotrexate(MTX),sunitinib(SUN)were respectively embedded in the micelles of biodegradable amphiphilic triblock copolymer poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide)(PDLLA-PEG-PDLLA),and the nano-doxorubicin micelles(NanoDOX),nano-methotrexate micelles(NanoMTX)and nano-sunitinib micelles(NanoSUN)with uniform size,good dispersion and stability were obtained.(2)Matrix metalloproteinases-2(MMP-2)-responsive polypeptides(GCRD-GPQG-IWGQ-DRCG)were used as cross-linking agents,and the nano-drug micelles were loaded into hyaluronic acid(HA)hydrogel by Michael addition reaction then MMP-responsive hydrogel drug sustained-release preparation was obtained.In vitro dissolution experiments showed that the drug release of drug-loaded hydrogels obviously response to MMP-2.Through in vivo degradation experiment,it was found that the drug-free hydrogels at tumor sites of nude mice were almost completely degraded after 14 days.(3)NanoDOX-loaded MMP-2-responsive hydrogels were cocultured with oral squamous cell carcinoma cell line(SCC-15),and in vitro antitumor efficacy of drug-loaded hydrogels was evaluated by cell uptake,cytotoxicity,apoptosis and wound healing test.It was found that NanoDOX-loaded hydrogels could better induce the apoptosis and inhibit the migration of SCC-15 cells.Further,after the nude mice xenograft model of oral squamous carcinoma(OSCC)established,drug-loaded hydrogels were injected into the tumor sites in situ,and the biological safety,pharmacokinetics and pharmacodynamics of the local drug delivery system were tested;Compared with the control group injected with free drug,the advantages and broad prospects of the local drug delivery system in OSCC chemotherapy were revealed.(4)NanoDOX-loaded or several nano-drug-loaded MMP-2-responsive hydrogels were cocultured with osteosarcoma cell line(MG-63),and the in vitro antitumor efficacy of single drug-loaded or combined drug-loaded hydrogels was evaluated by cell uptake,cytotoxicity,apoptosis and wound healing test.It was found that the combined drug-loaded hydrogels showed better performance under drug synergistic.Further,after the nude mice xenograft model of osteosarcoma and the local tumor recurrence nude mice model of osteosarcoma established,single drug-loaded and combined drug-loaded hydrogels were injected into the tumor sites or the tumor resection sites in situ,and the biological safety,pharmacokinetics,pharmacodynamics and tumor recurrence prevention ability of the local drug delivery system were tested;Compared with the control group injected with free drug or single drug-loaded hydrogels,the advantages and broad prospects of the local combined drug delivery system in osteosarcoma chemotherapy and postoperative prevention were revealed.